Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila

Abstract

Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

“…Interestingly, excessive activation of the Imd immune pathway can result in increased mortality caused by viral infections. Such reduced viability was observed in diedel (die) mutants of Drosophila after infection with SINV virus (but not with other RNA viruses such as VSV, DCV, CrPV and FHV) in the absence of increases in viral titers [150]. Diedel is a small (12 kDa) secreted factor produced in the fat body that is highly induced following SINV and VSV infection (while only SINV-induced mortality is sensitive to die mutations).…”

“…Transcriptome analysis reveals increased expression of immune-related genes in die mutants in the absence of infection that can be correlated with reduced viability. During SINV infection, genes in the Imd pathway are much more strongly induced in die mutants which was implicated in the pathological effects since the pathology phenotype was rescued in double mutants of die and genes in the Imd pathway (key, imd) [150]. Diedel is therefore considered an important regulatory point to "dampen" the immune response and to protect against tissue damage.…”

“…Tight control of JAK/STAT signaling is necessary to achieve an efficient antiviral immune response since both repression and over-stimulation can result in increased mortality [37,151]. As already discussed above (section 3.3), negative control mechanisms were also reported to prevent excessive activation of the Imd pathway and its possible associated immunopathology [150,167].…”

“…Pvf2 activates the tyrosine receptor kinase PVR and ERK signaling in enterocytes to block enteric viral infections. Diedel is also a secreted factor induced by particular viral infections (section 3.3) but involved in the dampening of the immune response associated with the Imd pathway to reduce tissue damage [150]. It is noted that the Unpaired ligands of the JAK/STAT pathway are induced during dicistrovirus infections, possible through stress signals and tissue damage [162], which can be interpreted as the activation of a systemic antiviral response.…”

WntD and Diedel: Two immunomodulatory cytokines inDrosophilaimmunity

“…36 A second interesting feature of Die is that homologs can be found in members of 3 unrelated families of large DNA viruses that infect lepidopterans, the Entomopoxviridae, Baculoviridae and Ascoviridae. die encodes a 12 kDa circulating protein secreted by the fat body upon infection.…”